Our overarching goal is to determine whether genetic markers can be used to optimize smoking cessation pharmacotherapy to enhance efficacy, medication adherence, and reduce side effects. Smoking is a leading cause of preventable death and disability, and smoking cessation reverses the risk of mortality. However, cessation failure is common despite available cessation medications, which are associated with different efficacy, side effects, adherence, use constraints, and costs. This challenge can be addressed by improving current treatments via personalized medicine based on individual genetic markers to maximize efficacy and minimize side effects. Our recent work suggesting that the nicotinic receptor gene CHRNA5 alters response to nicotine replacement therapy (NRT) has been replicated in a meta-analysis. Our new preliminary data suggest that CHRNA5 may be a useful marker for medication choice, because patients with CHRNA5 variant rs16969968 AA/GA genotypes may benefit from NRT and those with GG genotypes (conferring poor response to NRT) may benefit from varenicline, a medication with higher cost and use restrictions. Similarly, other genetic variation such as the nicotine metabolism gene CYP2A6 also alters response to NRT. Currently there is insufficient evidence to support the clinical use of genotype based smoking cessation treatment, because these findings are based on retrospective pharmacogenetic analyses of different trials with markedly different placebo and counseling effect sizes and dissimilar designs. For clinical translation, we need head to head comparison of state-of-the-art interventions, use of key genotypes implicated by current research, and valid assessments of side effects/ adherence. We propose a first, prospective, genotype-based stratified randomization trial to compare the two most effective smoking cessation medications (combination NRT [patch and lozenge], varenicline vs. placebo for 3 months) in 720 smokers with known genotypes. Leveraging the Principal Investigator's observational genetic follow-up study of smoking cessation with existing genotypes, this study uses a stratified randomization trial design based on a subject's pertinent genotype for smoking cessation. Specifically, in Aim 1, we will determine if CHRNA5 genotype moderates the effect of medication (combination NRT, varenicline, vs. placebo) on abstinence. In Aim 2, we will determine if CHRNA5 genotype predicts medication adherence and side effects. In Aim 3, we will incorporate multiple genotypes and other predictors in order to develop a clinical treatment assignment algorithm for cessation success. This proposal is an innovative smoking cessation trial leveraging existing genotyped smokers and a genotype-based randomization design to build the evidence base to support a genotype based algorithm that can optimize smoking cessation pharmacotherapy in terms of efficacy, side effects, adherence, and improve overall smoking cessation success. This work can result in improved physician care of patients who smoke, overall smoking cessation success, and prevention of cancer, heart, and lung disease.